The present invention relates to processes for the preparation of xcex2-alanine derivative. More particularly, it relates to processes for the preparation of xcex2-alanine derivative which is glycoprotein IIb/IIIa antagonist, inhibitor of blood platelets aggregation and inhibitor of the binding of fibrinogen to blood platelets.
In PCT WO95/08536, the processes for producing xcex2-alanine derivative which is useful as glycoprotein IIb/IIIa antagonist and inhibitor of platelet aggregation are disclosed.
The object of the present invention is to provide the producing process by which xcex2-Alanine derivative, shown the following formula [I] or [II] or a salt thereof, can be produced in a good yield.
The present invention provides a process for producing the xcex2-Alanine derivative illustrated in the Processes 1 and 2 as shown below. 
wherein
R1 is amino protective group,
R2 is acyl group, and
R3 is protected carboxy.
Among the compounds (I), (II) and (III), some compounds are novel, and some are known. They can be prepared from the known compounds in a conventional manner in this field of the art or the similar manners to those disclosed in Preparations and/or Examples mentioned later in the present specification.
Suitable salts of the object compound (I) are conventional pharmaceutically acceptable and non-toxic salts, and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.] and the like.
In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows:
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
The term xe2x80x9chigherxe2x80x9d is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
The preferable number of the xe2x80x9cone or morexe2x80x9d in the term xe2x80x9cone or more suitable substituent(s)xe2x80x9d may be 1 to 3.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may be carboxy protected by a conventional protecting group such as an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, isopentyl ester, hexyl ester, isohexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower-alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] or mono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.];
higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.];
lower alkenyl ester [e.g. (C2-C6)alkenyl ester (e.g. vinyl ester, allyl ester, etc.)];
lower alkynyl ester [e.g. (C2-C6)alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.)];
ar(lower)alkyl ester which may have one or more suitable substituent(s) [e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl, (e.g. benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(nethoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)];
aryl ester which may have one or more suitable substituent(s) [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen, (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.), indanyl ester, etc.];
cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cycloheptyloxycarbonyloxy]ethyl ester, etc.) etc.];
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl 2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or 2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like.
Among them, the preferred one may be lower alkyl ester, ar(lower)alkyl ester, aryl ester which may have one or more suitable substituent(s), cycloalkyloxycarbonyloxy(lower)alkyl ester or lower alkanoyloxy(lower)alkyl ester,
and the more preferred one may be methyl ester, ethyl ester, butyl ester, pentyl ester, isopentyl ester, isohexyl ester, benzyl ester, phenethyl ester, phenyl ester, indanyl ester, pivaloyloxymethyl ester or 1-cyclohexyloxycarbonyloxyethyl ester.
Suitable xe2x80x9camino protective groupxe2x80x9d may include acyl group as explained below, a conventional protective group such as ar(lower)alkyl which may have 1 to 3 suitable substituent(s) (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc.), [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, etc.] or the like; and the like.
Suitable xe2x80x9cacyl groupxe2x80x9d and xe2x80x9cacylxe2x80x9d may include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.
Suitable example of said xe2x80x9cacyl groupxe2x80x9d may be illustrated as follows:
aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); or the like;
aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(C1-C6)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C1-C6)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar(lower)alkenoyl [e.g., phenyl(C3-C6)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(C3-C6)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.);
ar(lower)alkoxycarbonyl [e.g., phenyl(C1-C6)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);
arylcarbamoyl (e.g., phenylcarbamoyl, etc.);
arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);
arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;
heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl; or the like; and the like.
Suitable xe2x80x9cheterocyclicxe2x80x9d moiety in the terms xe2x80x9cheterocycliccarbonylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkenoylxe2x80x9d and xe2x80x9cheterocyclicglyoxyloylxe2x80x9d as mentioned above, and xe2x80x9cheterocyclic groupxe2x80x9d mean saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. Among them, the preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1-H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
The acyl moiety as mentioned above may have one to ten, same or different, suitable substituent(s) such as
lower alkyl (e.g., methyl, ethyl, propyl, etc.);
lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);
lower alkylthio (e.g., methylthio, ethylthio, etc.);
lower alkylamino (e.g., methylamino, ethylamino, propylamino, etc.);
cyclo(lower)alkyl [e.g. cyclo(C3-C6)alkyl (e.g. cyclopentyl, cyclohexyl, etc.]);
cyclo(lower)alkenyl [e.g. cyclo(C3-C6)alkenyl (e.g., cyclohexenyl, cyclohexadienyl, etc.);
halogen (e.g., fluorine, chlorine, bromine, iodine); amino; amino protective group as mentioned above; hydroxy; protected hydroxy as mentioned below; cyano; nitro; carboxy; protected carboxy as mentioned above; sulfo; sulfamoyl; imino; oxo;
amino(lower)alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.), or the like.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
The more preferred example of xe2x80x9camino protective groupxe2x80x9d may be lower alkoxycarbonyl or ar(lower)alkoxycarbonyl, and the most preferred one may be t-butoxycarbonyl or benzyloxycarbonyl.
Suitable xe2x80x9cacyl groupxe2x80x9d of R2 can be referred to aforementioned xe2x80x9cacyl groupxe2x80x9d. Among them, the more preferred one may be lower alkanoyl, and the most preferred one may be acetyl.
The processes of the present invention are explained in detail in the following.
Process 1
The object compound (I) or a salt thereof can be prepared by subjecting a compound (II) or a salt thereof to elimination reaction of carboxy protective group, and then the acylation reaction of amino group.
The Elimination Reaction of Carboxy Protective Group
This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. lithium, sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like. Among them, the preferred one may be lithium anhydride.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like, is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium, sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ulman copper, etc.] and the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The Acylation Reaction of Amino Group
Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula
R2xe2x80x94OHxe2x80x83xe2x80x83(IV)
(wherein R2 is acyl as mentioned before) or its reactive derivative, or a salt thereof.
Suitable reactive derivative at the amino group of the compound obtained by elimination reaction of carboxy protective group mentioned above may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with a silyl compound such as N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (IV) may include an acid halide, an acid anhydride (e.g., acetic anhydride, etc.), an activated ester, and the like. Among them, the preferred one may be acid anhydride, and most preferred one may be acetic anhydride. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2+Nxe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reactive derivatives can optionally be selected from them accordingly to the kind of the compound obtained by elimination reaction of carboxy protective group mentioned above to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
When the compound obtained by elimination reaction of carboxy protective group mentioned above is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,N-carbonyl-bis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal, bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process 2
The object compound (III) or a salt thereof can be prepared by subjecting a compound (I) or a salt thereof to elimination reaction of the amino protective group.
This reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
When the object compound (III) thus obtained is in a salt form, it can be converted into a free form in a conventional manner (e.g., neutralization, column chromatography, recrystallization, desalting resin column chromatography, etc.).
The compounds obtained by the above Processes 1 and 2 can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, reprecipitation or the like.
It is to be noted that each of the compounds (I), (II) and (III) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
The compounds (I), (II) and (III) or a salt thereof include solvated compound [e.g., enclosure compound (e.g., hydrate, etc.)].
The compounds (I), (II) and (III) or a salt thereof include both its crystal form and non-crystal form.
The above invention would make it possible to produce xcex2-alanine derivative in a good yield and/or to obtain a certain stereoisomer thereof which has a specific configuration in a good yield.
The compound (I) or a salt thereof is useful as an intermediate for preparing the compound (III) or a salt thereof.
So, the production of the compound (I) or a salt thereof in a good yield is useful as the effective production of the intermediate for the compound (III) or a salt thereof which is useful as glycoprotain IIb/IIIa antagonist or so.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
A mixture of 2(S)-benzyloxycarbonylamino-xcex2-alanine (3.0 g) and p-toluenesulfonic acid monohydrate (2.88 g) in benzyl alcohol (15 ml) was heated to 120xc2x0 C. in the flask fitted with Dean-Stark equipment. After dissolved, toluene (90 ml) was poured into it, and the mixture was refluxed for 3.5 hours. The mixture was cooled down to room temperature, and concentrated in vacuo. The residue was resolved in ethyl acetate, washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, and evaporated in vacuo. The product was resolved in ethyl acetate (50 ml), and cooled to 0xc2x0 C. To the stirred solution, 4Nxe2x80x94HCl in ethyl acetate (2.13 ml) was added dropwise at 0xc2x0 C., then concentrated in vacuo. The oily product was solidified by addition of a mixture of ethyl acetate and isopropyl ether (1:1). The solid was washed with isopropyl ether, and dried in vacuo to give 2(S)-benzyloxycarbonylamino-xcex2-alanine benzyl ester hydrochloride (2.75 g).
NMR (DMSO-d6, xcex4): 3.04-3.29 (2H, m), 4.42-4.53 (1H, m), 5.02-5.17 (4H, m), 7.35 (5H, s), 7.37 (5H, s), 7.95 (1H, d, J=8.4 Hz)
MASS (m/z): 329 (M+ free+1)
To a suspension of 2(S)-benzyloxycarbonylamino-xcex2-alanine (2.0 g) in a mixture of dioxane (14 ml), water (7 ml) and 1N aqueous NaOH (6.94 ml) was added di-tert-butyl dicarbonate (1.67 g) at 0xc2x0 C. After 10 minutes, the temperature was allowed to reach to room temperature, and the mixture was stirred for 5 hours. The reaction mixture was evaporated in vacuo to remove dioxane, adjusted to pH 3.0 with aqueous 20% KHSO4, then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The resulting solid was washed with diethyl ether to give N-tert-butoxycarbonyl-2(S)-benzyloxycarbonylamino-xcex2-alanine (2.28 g).
NMR (CDCl3, xcex4): 1.42 (9H, s), 3.44-3.67 (2H, m), 4.34-4.42 (1H, m), 5.13 (2H, s), 7.30-7.36 (5H, m)
To a stirred solution of iodobenzene diacetate (7.26 g) in a mixture of ethyl acetate (44 ml), acetonitrile (44 ml) and water (22 ml) was added 2(R)-benzyloxycarbonylamino-succinamic acid (5.0 g) at ambient temperature. After stirred for 3 hours, the reaction mixture was cooled to 5xc2x0 C., followed by stirring for 2 hours. Insoluble material was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 2(R)-benzyloxycarbonylamino-xcex2-alanine (4.15 g) as a white solid.
IR (KBr): 3303.5, 3027.7, 2948.6, 1693.2, 1656.5, 1623.8, 1592.9, 1542.8 cmxe2x88x921 
NMR (D2O-TFA, xcex4): 3.35 (1H, dd, J=13.4 and 8.7 Hz), 3.57 (1H, dd, J=13.4 and 5.3 Hz), 4.57 (1H, dd, J=8.7 and 5.3 Hz), 5.16 (2H, s), 7.43 (5H, s)
MASS (m/z): 239 (M+H)+
mp: 238xc2x0 C. (dec.)
[xcex1]D31: 8.6xc2x0 (c=1.0, 1N NaOH aq.)
Thionyl chloride (3.22 ml) was added dropwise to methanol (25 ml) at 4xc2x0 C. under a nitrogen atmosphere. After stirred for 30 minutes, to the reaction mixture was added 2(R)-benzyloxycarbonylamino-xcex2-alanine (3 g), followed by warming to the ambient temperature and stirring overnight. The insoluble material was collected by filtration, washed with diisopropyl ether, and dried under a reduced pressure to give 2(R) -benzyloxycarbonylamino-xcex2-alanine methyl ester hydrochloride (3.15 g) as a white solid.
IR (KBr): 3365.2, 3317.0, 2950.5, 2885.0, 2850.3, 1733.7, 1695.1, 1594.8, 1537.0 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 3.00-3.24 (2H, m), 3.68 (3H, s), 4.39-4.51 (1H, m), 5.07 (2H, s), 7.73 (5H, s), 7.94 (1H, d, J=8.2 Hz)
MASS (m/z): 253 (M+H)+
mp: 166.0-166.5xc2x0 C.
[xcex1]D30: 39.2xc2x0 (c=1.0, MeOH)
The following compounds [Preparation 5 and 6] were obtained according to a similar manner to that of Preparation 4.
IR (KBr): 3322.7, 2863.8, 1727.9, 1695.1, 1596.8, 1540.8 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.18 (3H, t, J=7.1 Hz), 3.06 (1H, dd, J=13.0 and 9.4 Hz), 3.22 (1H, dd, J=13.0 and 4.7 Hz), 4.13 (2H, q, J=7.1 Hz), 4.36-4.48 (1H, m), 5.08 (2H, s), 7.37 (5H, s), 7.94 (1H, d, J=8.2 Hz)
MASS (m/z): 267 (M+H)+
mp: 141.0-141.5xc2x0 C.
[xcex1]D30: 39.9xc2x0 (c=1.0, MeOH)
IR (KBr): 3324.7, 2869.6, 1727.9, 1695.1, 1596.8, 1540.8 cmxe2x88x921 
NMR (DMSO-d6, xcex4) 1.18 (3H, t, J=7.1 Hz), 3.06 (1H, dd, J=13.0 and 9.4 Hz), 3.22 (1H, dd, J=13.0 and 4.7 Hz), 4.13 (2H, q, J=7.1 Hz), 4.36-4.48 (1H, m), 5.08 (2H, s), 7.37 (5H, s), 7.94 (1H, d, J=8.2 Hz)
MASS (m/z): 267 (M+H)+
mp: 141.3-141.8xc2x0 C.
[xcex1]D30: xe2x88x9239.1xc2x0 (c=1.0, MeOH)
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (20.0 g), 2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester hydrochloride (17.2 g) and 1-hydroxybenzotriazole (8.07 g) in N,N-dimethylformamide (200 ml) was added dropwise 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10.9 ml) at 0xc2x0 C. The mixture was stirred at 4xc2x0 C. for 15 hours, then poured into ice water (500 ml), and extracted with ethyl acetate (500 mlxc3x972). The combined organic layer was successively washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (from 1:1 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester (30.5 g) as a colorless oil.
IR (KBr): 3307, 2933, 1724, 1689, 1535, 1434, 1365, 1272, 1243, 1164 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.97-1.38 (2H, m), 1.46 (9H, s), 1.53-1.67 (7H, m), 2.27-2.67 (6H, m), 3.23-3.39 (3H, m), 3.69 (3H, s), 3.54-3.61 (1H, m), 4.07-4.14 (4H, m), 4.46-4.51 (1H, m), 5.12 (2H, s), 6.39-6.43 (1H, m), 7.32-7.35 (5H, m)
MASS (m/z): 503 (Mxe2x88x92Boc+2)+
The following compounds [Preparation 8 to 13] were obtained according to a similar manner to that of Preparation 7.
NMR (CDCl3, xcex4): 0.98-1.84 (11H, m), 1.45 (9H, s), 2.30-2.38 (3H, m), 2.59-2.71 (2H, m), 3.32-4.10 (8H, m), 3.76 (3H, s), 4.40-4.50 (1H, m), 5.09 (1H, ABq, J=12.3 Hz), 5.13 (1H, ABq, J=12.3 Hz), 7.31-7.37 (5H, m)
MASS (m/z): 625 (M+Na)+
NMR (CDCl3, xcex4) 0.97-1.77 (11H, m), 1.46 (9H, s), 2.35-2.68 (5H, m), 3.27-4.21 (8H, m), 3.70 (3H, s), 4.47-4.53 (1H, m), 5.13 (2H, s), 7.32-7.38 (5H, m)
MASS (m/z): 625 (M+Na)+
IR (KBr): 1720, 1710, 1691, 1651 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.92-1.15 (2H, m), 1.25-2.67 (15H, m), 1.46 (9H, s), 3.12-4.24 (7H, m), 4.46-4.58 (1H, m), 5.00-5.18 (4H, m), 6.40 (1H, d, J=9.3 Hz), 7.23-7.37 (10H, m)
MASS (m/z): 701 (M+Na)+
IR (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1652.7, 1535.1 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.89-1.90 (11H, m) , 1.18 (3H, t, J=7.1 Hz), 1.38 (9H, s), 2.20-2.80 (6H, m), 2.80-3.60 (3H, m), 3.65-4.45 (7H, m), 5.04 (2H, s), 7.31 (1H, dd, J=8.0 and 3.8 Hz), 7.95-8.10 (1H, m)
MASS (m/z): 639 (M+Na)+
IR (KBr): 3309.2, 2935.1, 2859.9, 1726.0, 1689.3, 1535.1 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.80-1.90 (11H, m), 1.38 (9H, s), 2.20-2.80 (6H, m), 2.80-4.00 (6H, m), 3.61 (3H, s), 4.10-4.45 (2H, m), 5.04 (2H, s), 7.36 (5H, s), 7.64 (1H, d, J=8.1 Hz), 7.95-8.15 (1H, m)
MASS (m/z): 603 (M+H)+, 625 (M+Na)+
IR (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1654.6, 1533.1 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.80-1.90 (11H, m), 1.17 (3H, t, J=7.1 Hz), 1.38 (9H, s), 2.20-2.80 (6H, m), 2.80-3.50 (3H, m), 3.65-4.45 (7H, m), 5.04 (2H, s), 7.36 (5H, s), 7.62 (1H, d, J=8.1 Hz), 7.95-8.10 (1H, m)
MASS (m/z): 617 (M+H)+, 639 (M+Na)+
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate (356 xcexcl) and 4-methylmorpholine (300 xcexcl) at xe2x88x9215xc2x0 C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester hydrochloride (783 mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between ethyl acetate and water. The organic layer was separated, washed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester (1.36 g) as a foam, which is the same compound obtained in Preparation 7.
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) and N,N-dimethylformamide (210 xcexcl) in dichloromethane (10 ml) was added dropwise oxalyl chloride (240 xcexcl) at 4xc2x0 C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester hydrochloride (940 mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide (10 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between a mixture of ethyl-acetate and n-hexane and water. The organic layer was separated, washed in turn with water, aqueous 5% NaHCO3 solution and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-xcex2-alanine methyl ester (0.89 g) as a foam, which is the same compound obtained in Preparation 15.
To a solution of N-(t-butoxycarbonyl)-2(S)-benzyloxycarbonylamino-xcex2-alanine (6.15 g) in methanol (120 ml) was added 10% Pdxe2x80x94C (50% wet, 1.2 g). The mixture was stirred vigorously, and hydrogen gas was bubbled for 1 hour. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (70 ml) and cooled to 0xc2x0 C. with ice bath. 1N NaOH (36 ml) was added, then acetic anhydride (3.77 ml) was added dropwise under stirring. The mixture was stirred for additional 1 hour at 0xc2x0 C., then the pH of the mixture was adjusted to 2.5 with aqueous 20% KHSO4. The resultant mixture was extracted with ethyl acetate-tetrahydrofuran (200 ml-100 ml) twice times. The combined organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N-(t-butoxycarbonyl)-2(S)-acetylamino-xcex2-alanine (3.17 g).
IR (KBr): 3370, 3303, 1707, 1689, 1612, 1552, 1513, 1431, 1386, 1369, 1309, 1277, 1254, 1173 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.37 (9H, s), 1.83, (3H, s), 3.21-3.27 (2H, m), 4.18-4.28 (1H, m), 6.75-6.85 (1H, m), 7.99 (1H, d, J=7.9 Hz)
MASS (m/z): 245 (Mxe2x88x92H)xe2x88x92
To a mixture of N-(t-butoxycarbonyl)-2(S)-acetylamino-xcex2-alanine (3.0 g) in dimethylformamide (60 ml) was added NaHCO3 (2.05 g) at xe2x88x922xc2x0 C., and a solution of benzyl bromide in dimethylformamide (60 ml) was added by using a dropping funnel under stirring. The mixture was stirred overnight around 26xc2x0 C., then poured into a mixture of ice-water (300 ml) and hexane-ethyl acetate (8:2, 500 ml). After the organic layer was separated, the aqueous layer was extracted again with hexane-ethyl acetate (8:2, 300 ml). The combined organic layer was washed with water (300 mlxc3x972), brine (300 ml) and dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (8:2) to give N-(t-butoxycarbonyl)-2(S)-acetylamino-xcex2-alanine benzyl ester (3.68 g).
IR (KBr): 3361, 3324, 1739, 1687, 1650, 1536, 1456, 1440, 1392, 1369, 1346, 1319, 1278, 1251, 1203, 1174 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.42 (9H, s), 2.03 (3H, s), 3.51-3.56 (2H, m), 4.60-4.68 (1H, m), 4.80 (1H, br), 5.18 (2H, s), 7.36 (5H, singlet like)
MASS (m/z): 237 (Mxe2x88x92Boc+2H)+
To an ice-cooled solution of N-(t-butoxycarbonyl)-2(S)-acetylamino-xcex2-alanine benzyl ester (3.44 g) in ethyl acetate (35 ml) was added 4N HCl in ethyl acetate (25.5 ml). The mixture was stirred for 2.5 hours at an ambient temperature, then the solvent was decanted. The residue was washed with diethyl ether several times, and dried in vacuo to give 2(S)-acetylamino-xcex2-alanine benzyl ester hydrochloride (2.31 g) as a white powder.
IR (KBr): 3413, 3245, 1739, 1660, 1612, 1537, 1500, 1454, 1377, 1307, 1220, 1166 cmxe2x88x921 
NMR (DMSO-d6, xcex4) 1.89 (3H, s), 3.03-3.28 (2H, m), 4.54-4.65 (1H, m), 5.15 (2H, s), 7.33-7.39 (5H, m), 8.25 (3H, br), 8.67 (1H, d, J=7.7 Hz)
MASS (m/z): 237 (M+H)+
To a solution of 2(S)-acetylamino-xcex2-alanine benzyl ester hydrochloride (1.86 g), N-(t-butoxycarbonyl)-3(R)-nipecotic acid (1.64 g) and 1-hydroxybenzotriazole (0.97 g) in dimethylformamide (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.31 ml) at 0xc2x0 C. The mixture was stirred for 2 hours at room temperature, then poured into ice water-ethyl acetate. The separated organic layer was washed with water, aqueous saturated NaHCO3, brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with CHCl3xe2x80x94MeOH (95:5) to give N-[(R)-1-(t-butoxycarbonyl)-3-piperidyl-carbonyl]-2(S)-acetylamino-xcex2-alanine benzyl ester (2.84 g).
IR (Film): 3300, 2938, 1741, 1666, 1648, 1552, 1533, 1469, 1434, 1367, 1301, 1265, 1241, 1151 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.46 (9H, S), 1.55-1.77 (4H, m), 2.04 (3H, s), 2.10-2.22 (1H, br), 3.10 (2H, br), 3.79 (2H, br), 3.64-3.67 (2H, m), 3.79-3.85 (1H, br), 4.62-4.71 (1H, m), 5.18 and 5.30 (total 2H, s), 7.26-7.40 (5H, m)
MASS (m/z): 348 (Mxe2x88x92Boc+2H)+
To an ice-cooled solution of N-[(R)-1-(t-butoxycarbonyl)-3-piperidylcarbonyl]-2 (S)-acetylamino-xcex2-alanine benzyl ester (2.7 g) was added 4N HCl in ethyl acetate (25.5 ml). The mixture was stirred for 2.5 hours at an ambient temperature, then the solvent was decanted. The residue was washed with diethyl ether several times, and dried in vacuo to give N-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-xcex2-alanine benzyl ester hydrochloride (2.29 g) as a white powder.
IR (Film): 3267, 3064, 2958, 1741, 1656, 1543, 1452, 1376 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.45-1.87 (4H, m), 1.91 (3H, s), 2.62-2.85 (3H, m), 3.09-3.46 (4H, m), 4.38-4.42 (1H, m), 5.01-5.14 (2H, m), 7.37-7.39 (5H, m), 8.37-8.41 (2H, m), 8.78 (1H, br), 8.98 (1H, br)
MASS (m/z): 348 (M+H)+